Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The protein kinases play a key role in growth factor signaling inducing cell growth, differentiation, and proliferation, and thus activities of the protein kinases affect almost all aspects of cellular life.
Abnormal cell signaling pathways due to mutations or overexpressions of protein kinases are closely connected with stroma diseases including from diseases that are comparatively not life-threatening, like psoriasis, to toxic (pathogenic) diseases, like cancers.
Protein kinases may be classified into tyrosine kinases (TKs) and serine-threonine kinases (STKs).
One of the main aspects of tyrosine kinases is its involvement with growth factor receptors. Growth factor receptors are cell-surface proteins. When bound to growth factor ligands, the growth factor receptors are converted to active forms, which interact with proteins on the inner surface of cell membranes. This leads to the phosphorylation on tyrosine residues of the receptor and other proteins and to the formation of complexes with a variety of cytoplasmic signaling molecules inside the cell that, in turn, affect numerous cellular responses such as cell growth, differentiation, and proliferation and metabolic effects to the extracellular microenvironment, etc (Schleessinger and Ullrich, Neuron. 9: 303-391(1992)).
Growth factor receptors with tyrosine kinase activity are known as receptor tyrosine kinases (RTKs). The receptor tyrosine kinases include a large family of trans-membrane receptors exhibiting diverse biological activities.
At present, at least 19 subfamilies of receptor tyrosine kinases have been identified, named “HER RTK” subfamily which includes epidermal growth factor receptor (EGFR), HER2, HER3, HER4, and the like. These receptor tyrosine kinases are composed of an extracellular glycosylated ligand binding domain, a transmembrane domain, and an intracellular cytoplasmic domain that can phosphorylate tyrosine residues on proteins.
Another receptor tyrosine kinase subfamily is composed of an insulin receptor (IR), an insulin-like growth factor I receptor (IGF-1R), and an insulin receptor related receptor (IRR). IR and IGF-1R interact with insulin, IGF-I, and IGF-II to form a heterotetramer of two completely extracellular-glycosylated α. subunits and two β subunits which cross the cell membrane and contain the tyrosine kinase domain.
Still another receptor tyrosine kinase subfamily is referred to as a platelet derived growth factor receptor (PDGFR) group, which includes PDGFRα, PDGFRβ, CSFIR, c-Kit, and c-Fms. These receptors are made up of glycosylated extracellular domains composed of variable numbers of immunoglobulin-like loops and an intracellular domain. A fetus liver kinase (Flk) receptor subfamily, which is included in the PDGFR group due to its similarity with the PDGFR subfamily, has been known. The Flk subfamily is composed of kinase insert domain-receptor fetal liver kinase-1 (KDR/FlK-1), Flk-1R, Flk-4, and Fms-like tyrosine kinase 1 or 3 (flt-1).
MET, which is a type of tyrosine kinase growth factor receptor family, is called c-Met, and has been considered to play a role in the primary canner growth and metastasis as a human hepatocyte growth factor receptor tyrosin kinase (hHGFR) (Plowman et al., DN&P, 7 (6):334-339(1994)).
In addition to the receptor tyrosine kinases (RTKs), there also exists a particular family of complete intracellular TKs called “non-receptor tyrosine kinases” or “cellular tyrosine kinases (CTK)”. The non-receptor tyrosine kinases do not contain extracellular and trans-membrane domains, and are composed of Src, Frk, Btk, Csk Abl, Zap70, Fes, Fak, Jak, and Ack subfamilies. Of these, the Src subfamily includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1 (Aurora-B), AUR2 (Aurora-A), AUR3 (Aurora-C), Yrk, and the like (Bolen, Oncogene. 8: 2025-2031(1993)).
Pathogenic diseases associated with the receptor tyrosine kinases and non-receptor tyrosine kinases include psoriasis, hepatic cirrhosis, diabetes, angiogenesis, restenosis, ocular diseases, rheumatoid arthritis, autoimmune diseases, atherosclerosis, kidney troubles, and the like.
Of the PKs described above, receptor tyrosine kinases, such as Bcr-Abl, EGFR, and VEGFR, have been heavily studied as favorable anticancer drug targets, and anticancer drugs, such as Gleevec or Iressa, have been developed and marketed.
In addition, many anticancer drugs targeting c-Met (hepatocyte growth factor receptor, HGFR), which is a hepatocyte growth factor/scatter factor (HGF/SF) receptor in the RTKs that have been studied as anticancer drug targets, have been developed (J. G. Christensen, J. Burrows et al., Cancer Letters, 2005, 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797).
c-Met is overexpressed or activated in many human cancers, such as lung cancer, gastric cancer, skin cancer, kidney cancer, colon cancer, and pancreatic cancer, involved in tumor progression and metastasis under tumor formation and increased cell mobility and invasiveness (J. G. Christensen et al., Cancer Letters, 225:1-26(2005); W. G. Jiang et al., Critical Reviews in Oncology/Hematology, 53:35-69(2005)). c-Met and its ligand HGF are expressed in many tissues, but in normal cases, expressions thereof are restricted in mainly epithelial and mesenchymal progenitor cells. c-Met and HGF/SF are needed in the growth of normal mammals, and have been found to be important for cell metastasis, cell proliferation and survival, morphogenetic differentiation, and organization of three-dimensional tubular structures (renal tubular cells, and line formation). HGF/SF is an angiogenesis factor, and the c-Met signaling in endothelial cells induces cell responses required for an angiogenesis (proliferation, mobility, and invasion).
It was found that c-Met and its ligand HGF, are co-expressed at increased levels in various human cancers. However, since receptors and ligands are normally expressed depending on different cell types, c-Met signaling is generally regulated by a tumor-stroma interaction in most cases.
In addition, gene amplification, mutation, and rearrangement of c-Met were observed in various human cancers. Families with germline mutations that activate c-Met kinase are prone to multiple kidney tumors as well as tumors in other tissues.
It was found that the expression of c-Met and/or HGF/SF is correlated with the state of disease progression of different types of cancers (lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovaries, stomach, skin, and bone cancers), and the overexpression of c-Met and/or HGF/SF is correlated with poor prognoses and disease outcomes in many major human cancers including lung, liver, gastric, and breast cancers. It was reported that c-Met is directly involved in cancers without a successful treatment regimen, such as pancreatic cancer, glioma, and hepatocellular cancer, and it was reported that the lung cancer caused by activation of ERBB3 signaling pathway has resistance against Gefitinib (product name: Iressa) through the overexpression of c-Met (J. A. Engelman, K. Zejnullahu et. al. Science, 316:1039-1043(2007)).
HGF/SF binds to an extracellular domain of c-Met to activate c-Met, and the activation of c-Met induces the tyrosine phosphorylation and downstream signaling through activations of PI3-kinase and Ras/MAPK mediated by Gab1 and Grb2, respectively, thereby inducing cell mobility and proliferation.
It was found that c-Met interacts with other proteins inducing receptor activation, transformation, and invasion, and it was reported that c-Met interacts with α6β4 integrin (a receptor to extracellular matrix (ECM), such as laminine) to promote HGF/SF dependent invasive growth.
Thus, the present inventors, while conducting studies for developing protein kinase inhibitors, experimentally observed that morpholino pyrimidine compounds with particular structures have an excellent effect of inhibiting protein kinases, such as c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, and Aurora-A, and thus can be useful for the prevention and treatment of hyper proliferative disorders thereof.
Throughout the entire specification, many papers and patent documents are referenced and their citations are represented. The disclosures of cited papers and patent documents are entirely incorporated by reference into the present specification, and the level of the technical field within which the present invention falls and details of the present invention are explained more clearly.